This presentation will review recent data on the pharmacokinetics and pharmacodynamics of weight-based taribavirin dosing and will discuss the potentialy beneficial risk-benefit profile of taribavirin relative to ribavirin.

The HCV genome encodes an RNA-dependent RNA polymerase (NS5B), which is responsible for the synthesis of new viral RNA strands. In this talk, an overview and update on our efforts to develop novel inhibitors of the HCV polymerase NS5B will be presented.

2:00 Nucleoside Approach to Inhibitors for HCV PolymeraseMichael Sofia, Ph.D., Vice President, Chemistry, Pharmasset, Inc.The presentation will discuss the current status of our clinical candidate R7128 and will present current data on our novel liver targeting inhibitor PSI-7851. A overview of the PSI-7851 design rationale and data supporting liver targeting will be highlighted. In addition, data supporting the development of PSI-7851 will be reviewed.

We previously disclosed the identification of several novel series of potent, non-nucleoside NS5B inhibitors containing a 1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazine moiety which bind to the “palm” site of the NS5B protein. Many of these molecules exhibited poor pharmacokinetic properties following oral administration to animals. We now describe new modifications that led to significantly improved oral bioavailability properties of the resulting compounds without sacrificing other desirable biological attributes.

3:00 Sponsored Presentation (Opportunity Available)

3:15 Networking Refreshment Break in the Exhibit Hall

Inhibitors of New Viral Targets

4:00 Small Molecule Approaches to NS4B and Other Novel Non-Structural Protein Targets

Jeffrey S. Glenn, M.D., Ph.D., Associate Professor of Medicine, Department of Gastroenterology and Hepatology; Director of Center for Hepatitis and Liver Tissue Engineering, Stanford University School of Medicine

NS4B plays an important role in establishing the HCV replication complex. Several key domains have been genetically validated as essential for NS4B’s function in HCV replication. This in turn has led to the development of small molecule approaches to targeting NS4B, including a new role for an old antihistamine.

Our small molecule entry inhibitors for HCV exhibit EC50 of <1 nM and >10000 fold therapeutic window in the infectious virus assays. The compounds act additively with the current standard of care (IFN and Ribavirin) as well a HCV protease inhibitor. A clinical development candidate has been selected based on in vivo PK and bioavailability parameters for further development. This class of compounds can add significantly to a drug cocktail targeting multiple steps of the viral life cycle, with the goal of completely eliminating virus infection.

We discuss helicase inhibitors as potential components of a multidrug therapy against HCV. Viral helicase, a part of NS3 protein, is necessary for the replication of the viral RNA. Helicase inhibitors were identified by fluoromeric assay of helicase activity in a subgenomic HCV replicon system in Huh-7 hepatoma cells. We demonstrated higher antiviral activities in the HCV replication system, together with low cytotoxicity, for compounds belonging to three different groups: acridone-4-carboxylic derivatives (EC50 in the range of 9-10 uM), amidinoanthracyclines (EC50 in the range of 0.01 – 0.14 uM) and tropolone derivatives (EC50 corresponding to 30-46 uM).